In animals, the recreational drug 3,4-methylenedioxymethamphetamine (MDMA) is a documented serotonin (5-HT) neurotoxin. Whether or not MDMA is also neurotoxic in humans is not known, but there is recent evidence that it is [human MDMA users have lower concentrations of the 5-HT metabolite, 5-HIAA, in their cerebrospinal fluid (CSF) than controls]. The difficulty in assessing the neurotoxic potential of MDMA in humans stems largely from the fact that there are no direct methods for investigating the status of 5-HT neutrons in the living human brain. Positron emission tomography (PET), when used in conjunction with a radioligand specific for the 5-HT neutron, is an imaging technique that could be used to study the status of 5-HT neutrons in humans during life. Indeed, preliminary observations suggest that PET imaging with the newly developed 5-HT transporter ligand [11C]McN-5652 is useful for detecting brain 5-HT deficits in MDMA-lesioned baboons. The overall goal of the present project is to confirm this finding and extend it to humans. To achieve this goal, two series of studies are proposed, one in baboons and another in humans. In preclinical studies, baboons will be lesioned with either MDMA or 2'-NH2-MPTP, an MPTP analog that, when administered with desmethylimipramine (DMI), is highly and selectively toxic to brain 5-HT neutrons. Baboons lesioned with MDMA, which is known to damage brain 5-HT systems in the entire forebrain, will be used for "between subjects" comparisons; baboons lesioned with 2'-NH2-MPTP, which should permit unilateral lesions of brain 5-HT systems, will be used for "within subjects" comparisons. Two, 36 and 72 weeks after lesioning, the animals will undergo PET studies with (11C]McN-5652 and lumbar punctures for CSF 5-HIAA determinations. The animals will then be sacrificed for direct determination of tissue 5-HT axonal markers. These studies will offer the unique opportunity to explore the relation between alterations in specific (11C]McN-5652 binding measured in vivo by means of PET and changes in tissue 5-HT neuronal markers (i.e., 5-HT, 5-HIAA, [3H]citalopram binding sites) measured directly in post-mortem tissue of the same animals. In a second set of studies, humans with a history of extensive MDMA use but drug-free for at least 4 weeks will undergo PET and CSF studies identical to those in baboons. Results obtained in MDMA users (MDMA group, n=18) will be compared to those obtained in individuals who have used drugs other than MDMA (NON-MDMA group, n= 18), as well as to those obtained in subjects without a history of drug abuse or dependence (NON- DRUG group, n=18). The purpose of these studies is to flip assess the status of central 5-HT neutrons in humans after MDMA exposure, and to extend to humans the observation that, in nonhuman primates, PET imaging with (11C]McN-5652 is useful for detecting MDMA-induced 5-HT neural injury during life. The long-term goals of this project are: 1) To further validate the usefulness of [11C]McN-5652 for studying 5-HT neurons in the living human brain with PET; and 2) To better serve the neurotoxic potential of MDMA in humans.